Summary Background Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody–drug conjugate ...containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). Methods In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1–2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m2 . Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov , number NCT01290549. Findings Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3–4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3–4 adverse events were neutropenia (18 40% of 45), anaemia (five 11%), and peripheral sensory neuropathy (four 9%). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3–4 adverse event, with neutropenia (five 56%), anaemia (two 22%), and febrile neutropenia (two 22%) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients two treatment related, and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Interpretation Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Funding Genentech.
Abstract We sought to examine the impact of calcific deposits on the outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). The outcomes of 1,476 consecutive CTO PCIs ...performed in 1,453 patients (65.5 ± 10 years; 85% male) between 2012 and 2016 at 11 US centers were evaluated. Moderate or severe quantity of calcium was present in 58% of target lesions. Calcified lesions were more tortuous and more likely to have proximal cap ambiguity and interventional collaterals. PCI of moderately/severely calcified CTOs more often required use of the retrograde approach (54% vs. 30%, p<0.001) and was associated with longer procedure and fluoroscopy time and higher air kerma radiation dose and contrast volume. Moderate/severe quantity of calcium was associated with lower technical (86.6% vs. 93.8%, p<0.001) and procedural (84.4% vs. 92.7%, p<0.001) success rates and higher incidence of major adverse cardiac events (3.7% vs. 1.8%, p=0.033). On multivariate analysis the presence of moderate/severe quantity of calcium was not independently associated with technical success. Balloon angioplasty was the most common lesion preparation technique for calcified lesions, followed by rotational atherectomy and laser. To conclude, in a contemporary, multicenter registry, moderate/severe calcific deposits were present in 58% of attempted CTO lesions and was associated with higher use of the retrograde approach, lower success and higher complication rates. However, on multivariable analysis the amount of calcium was not independently associated with technical success.
Summary Background Treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited. CUDC-907 is an oral, first-in-class, small molecule that is designed to ...inhibit both histone deacetylase (HDAC) and PI3K enzymes, which are members of common oncogenic pathways in haematological malignancies. We aimed to assess overall safety and preliminary activity in this dose-escalation study of CUDC-907 monotherapy in patients with relapsed or refractory lymphoma and multiple myeloma. Methods This open-label, first-in-man, phase 1 trial recruited adult patients (aged ≥18 years) with lymphoma or multiple myeloma who were refractory to or had relapsed after two or more previous regimens, from four US cancer centres. CUDC-907 was orally administered in a standard 3 + 3 dose-escalation design at four different dosing schedules, to which participants were sequentially assigned as follows: once daily, intermittently (twice or three times weekly; simultaneous enrolment), and daily for 5 days followed by a 2-day break (5/2), in 21-day cycles. Dosing started at 30 mg for the once-daily schedule and 60 mg for other schedules, escalating in 30 mg increments. Patients continued to receive CUDC-907 until disease progression or until other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose, assessed in patients who received at least 66% of cycle 1 doses without modification and those who had a dose-limiting toxicity (DLT) in cycle 1 irrespective of dose modification. We assessed safety in all patients who received at least one dose of study drug. This ongoing trial is registered at ClinicalTrials.gov , number NCT01742988. Findings Between Jan 23, 2013, and July 27, 2015, we enrolled 44 patients, of whom ten were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to three-times-weekly (MTD 150 mg), and seven to the 5/2 dosing schedule (MTD 60 mg). 37 (84%) patients had discontinued study drug as a result of progressive disease or clinical signs of progressive disease at the data cutoff. Four DLTs occurred in three of 40 DLT-evaluable patients (diarrhoea and hyperglycaemia in one patient on 60 mg once daily, hyperglycaemia in one patient on 150 mg twice weekly, and diarrhoea in one patient on 150 mg three times weekly); no DLTs were reported in patients on the 5/2 schedule. Grade 3 or worse adverse events occurred in 19 (43%) of 44 patients, the most common of which were thrombocytopenia (in nine 20% of 44 patients), neutropenia (three 7%), and hyperglycaemia (three 7%). 11 (25%) of 44 patients had serious adverse events, three of which were regarded as treatment related (epistaxis and the DLTs of diarrhoea and hyperglycaemia). Adverse events led to dose reductions in six (14%) patients and treatment discontinuation in seven (16%). Five (14%) of 37 response-evaluable patients achieved an objective response (two complete responses and three partial responses). All five responses occurred in the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; n=9), and three occurred in those with transformed follicular lymphoma DLBCL (n=5). 21 (57%) of 37 response-evaluable patients had stable disease, including those with DLBCL, Hodgkin's lymphoma, and multiple myeloma. On the basis of these findings, we selected CUDC-907 60 mg on the 5/2 dosing schedule as the recommended phase 2 dose. Interpretation The safety and tolerability profile of CUDC-907 and the promising preliminary evidence of response support continued development of CUDC-907 at the 60 mg 5/2 dosing schedule, alone and in combination with other therapies. A dose-expansion trial of this dose in patients with refractory and relapsed DLBCL in particular, is ongoing. Funding Curis, Inc, and the Leukemia and Lymphoma Society.
COVID-19-associated mucormycosis (CAM) is a recently emerging entity. There is a lack of reports of CAM in organ transplant recipients.
We conducted a multicenter (n = 18) retrospective research in ...India during November 2020 to July 2021. The purpose of this study was to explore the clinical spectrum, outcome and risk factors for mortality of CAM in kidney transplant recipients (KTRs).
The incidence of CAM was 4.4% (61/1382 COVID-19-positive KTRs) with 26.2% mortality. The median age of the cohort was 45 (38-54) y. Twenty (32%) were not hospitalized and 14 (22.9%) were on room air during COVID-19. The proportion of postdischarge CAM was 59.1%, while concurrent CAM was reported in 40.9%. The presentation of CAM was 91.8% rhino-orbital-cerebral mucormycosis and 8.2% pulmonary with 19.6% and 100% mortality, respectively. In the univariable analysis, older age, obesity, difficulty of breathing, high-flow oxygen requirement, and delay in starting therapy were significantly associated with mortality. In the multivariable logistic regression analysis, patients requiring high-flow oxygen therapy odds ratio (95% confidence interval) = 9.3 (1.6-51);
= 0.01 and obesity odds ratio (95% confidence interval) = 5.2 (1-28);
= 0.05 was associated with mortality. The median follow-up of the study was 60 (35-60) d.
We describe the largest case series of CAM in KTRs. Morality in pulmonary CAM is extremely high. Severe COVID-19 pose extra risk for the development of CAM and associated mortality. Our report will help in better understanding the conundrum and management of CAM.
We sought to examine the impact of previous failure on the outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). We examined the clinical and angiographic ...characteristics and procedural outcomes of 1,213 consecutive patients who underwent 1,232 CTO PCIs from 2012 to 2015 at 12 US centers. Mean age was 65 ± 10 years, and 84.8% of patients were men. A previously failed attempt had been performed in 215 patients (17.5%). As compared with patients without previous CTO PCI failure, patients with previous failure had higher Multicenter CTO Registry in Japan CTO score (2.40 ± 1.13 vs 3.28 ± 1.29, p <0.0001) and were more likely to have in-stent restenosis (10.5% vs 28.4%, p <0.0001) and to undergo recanalization attempts using the retrograde approach (41% vs 50%, p = 0.011). Technical (90% vs 88%, p = 0.390) and procedural (89% vs 86%, p = 0.184) success were similar in the 2 study groups; however, median procedure time (125 vs 142 minutes, p = 0.026) and fluoroscopy time (45 vs 55 minutes, p = 0.015) were longer in the previous failure group. In conclusion, a previously failed CTO PCI attempt is associated with higher angiographic complexity, longer procedural duration, and fluoroscopy time, but not with the success and complication rates of subsequent CTO PCI attempts.
Given finite ICU bed capacity, knowledge of ICU bed utilization during the coronavirus disease 2019 pandemic is critical to ensure future strategies for resource allocation and utilization. We sought ...to examine ICU census trends in relation to ICU bed capacity during the rapid increase in severe coronavirus disease 2019 cases early during the pandemic.
Observational cohort study.
Thirteen geographically dispersed academic medical centers in the United States.
We obtained daily ICU censuses from March 26 to June 30, 2020, as well as prepandemic ICU bed capacities. The primary outcome was daily census of ICU patients stratified by coronavirus disease 2019 and mechanical ventilation status in relation to ICU capacity.
None.
Prepandemic overall ICU capacity ranged from 62 to 225 beds (median 109). During the study period, the median daily coronavirus disease 2019 ICU census per hospital ranged from 1 to 84 patients, and the daily ICU census exceeded overall ICU capacity for at least 1 day at five institutions. The number of critically ill patients exceeded ICU capacity for a median (interquartile range) of 17 (12-50) of 97 days at these five sites. All 13 institutions experienced decreases in their noncoronavirus disease ICU population, whereas local coronavirus disease 2019 cases increased. Coronavirus disease 2019 patients reached their greatest proportion of ICU capacity on April 12, 2020, when they accounted for 44% of ICU patients across all participating hospitals. Maximum ICU census ranged from 52% to 289% of overall ICU capacity, with three sites less than 80%, four sites 80-100%, five sites 100-128%, and one site 289%.
From March to June 2020, the coronavirus disease 2019 pandemic led to ICU censuses greater than ICU bed capacity at fives of 13 institutions evaluated. These findings demonstrate the short-term adaptability of U.S. healthcare institutions in redirecting limited resources to accommodate a public health emergency.
Study objective Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering ...progesterone to patients with acute traumatic brain injury. Methods This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale–Extended 30 days postinjury. Results Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale–Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo. Conclusion In this small study, progesterone caused no discernible harm and showed possible signs of benefit.
Summary Background Concerns exist about whether monovalent (RV1) and pentavalent (RV5) rotavirus vaccines provide adequate protection against diverse strains and whether vaccine introduction will ...lead to selective pressure. We aimed to investigate the distribution of rotavirus strains and strain-specific rotavirus vaccine effectiveness after vaccine introduction. Methods We did a systematic review of published work to assess the strain-specific effectiveness of RV1 and RV5 rotavirus vaccines. We classified strains as homotypic, partly heterotypic, and fully heterotypic based on the amount of antigen-matching between strain and vaccine. When studies reported vaccine effectiveness against single antigens (G-type or P-type), we categorised them as either single-antigen vaccine type or single-antigen non-vaccine type. Our primary outcome was strain-specific vaccine effectiveness, comparing effectiveness of homotypic strains with fully or partly heterotypic strains. A secondary outcome was the prevalence of rotavirus strains after vaccine introduction. We estimated pooled odds ratios using random-effect regression models, stratified by country income level and vaccine type, and tested for differences in strain-specific vaccine effectiveness. We assessed strain distribution trends from surveillance reports. Findings In high-income countries, RV1 pooled vaccine effectiveness was 94% (95% CI 80–98) against homotypic strains, 71% (39–86) against partly heterotypic strains, and 87% (76–93) against fully heterotypic strains. In middle-income settings, respective pooled data were 59% (36–73), 72% (58–81), and 47% (28–61). In high-income countries, RV5 vaccine effectiveness was 83% (78–87) against homotypic strains, 82% (70–89) against single-antigen vaccine type strains, 82% (70–89) against partly heterotypic strains, and 75% (47–88) against single-antigen non-vaccine type strains. In middle-income settings, RV5 vaccine effectiveness was 70% (58–78) against single-antigen vaccine type strains, 37% (10–56) against partly heterotypic strains, and 87% (38–97) against single-antigen non-vaccine type strains. No difference was noted in vaccine effectiveness for either RV1 or RV5 in any setting (all p>0·05). Prevalent strains in countries using RV1 were G2P4 (2198 of 4428, 50%) and G1P8 (953, 22%), and those in countries using RV5 were G1P8 (1280 of 3875, 33%) and G2P4 (1169, 30%). Sustained predominance of a single strain was not recorded. Interpretation RV1 and RV5 exert similar effectiveness against homotypic and heterotypic rotavirus strains. Persistence of specific strains was not recorded, suggesting vaccine-induced selective pressure did not occur. Expansion of rotavirus surveillance efforts to low-income countries and ongoing surveillance are crucial to identify emergence of new strains and to assess strain-specific vaccine effectiveness in various settings. Funding None.
Abstract Background We sought to determine the effect of lesion age on procedural techniques and outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Methods We ...examined the characteristics and outcomes of 394 CTO PCIs with data on lesion age, performed between 2012 and 2016 at 11 experienced US centres. Results Mean patient age was 66 ± 10 years and 85.6% of the patients were men. Overall technical and procedural success rates were 90.1% and 87.5%, respectively. A major adverse cardiovascular event (MACE) occurred in 16 patients (4.1%). Mean and median lesion ages were 43 ± 62 months and 12 months (interquartile range, 3-64 months), respectively. Patients were stratified into tertiles according to lesion age (3-5, 5-36.3, and > 36.3 months). Older lesion age was associated with older patient age (68 ± 8 vs 65 ± 10 vs 64 ± 11 years; P = 0.009), previous coronary artery bypass grafting (62% vs 42% vs 30%; P < 0.001), and moderate/severe calcification (75% vs 53% vs 59%; P = 0.001). Older lesions more often required use of the retrograde approach and antegrade dissection/re-entry for successful lesion crossing. There was no difference in technical (87.8% vs 89.6% vs 93.0%; P = 0.37) or procedural (86.3% vs 87.4% vs 89.0%; P = 0.80) success, or the incidence of MACE (3.1% vs 3.0% vs 6.3%; P = 0.31) for older vs younger occlusions. Conclusions Older CTO lesions exhibit angiographic complexity and more frequently necessitate the retrograde approach or antegrade dissection/re-entry. Older CTOs can be recanalized with high technical and procedural success and acceptable MACE rates. Lesion age appears unlikely to be a significant determinant of CTO PCI success.
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